TRPC and TRPM channels: New possible targets for cancer

Abstract

Cancer is the second most common reason for death in the world. The cancer research over four decades has been reached to the prospective on dysregulation of ions like (Ca²⁺, Mg²⁺, Na⁺, K+, or Cl^-) recently. These ions are orchestrated through numerous proteins, ion channels, selectively or non-selectively. However, the dysregulation of these ions and their channel expression are being reported for various diseases but here we have reviewed precisely TRP channels (TRPC and TRPM) for their role in cancer. The transient receptor potential (TRP) channels were first discovered in Drosophila melanogaster in 1989 and since then the superfamily becomes a group of 30 members under six subsections. Interestingly, we found that the TRPC (Canonical) channels, with 6 members, were explored in nine different types of cancers in last two decades. Additionally, we included the TRPM (Melastatin) subfamily and reviewed their role in cancer. Conclusively, these studies support that TRP channel-based therapies must be taken forward for clinical studies. Some channels, such as TRPC6, TRPM7 and TRPM8 were explored extensively in many cancer types which may be a potential target for cancer treatment. However, TRPM8 in lung cancer was reported for reverse association with cell proliferation, which needs to be reverified in lung cancer and other cancers. Besides, some TRPC channels are associated with store-operated calcium entry (SOCE) such as TRPC1, TRPC4 and TRPC6. Interestingly, the TRPC6 role was reported in breast cancer for modulation of Ca²⁺ through translocation of Orai1 and Orai3.

Keywords

Ion channel TRP channels Cancer Migration acidic extracellular pH

1 Introduction

Ion channels play a decisive role in harmonizing numerous ions (Ca²⁺, Mg²⁺, Na⁺, K+, or Cl^-) regulate cell growth and immune response [1 –4]. The homeostasis of these ions is crucial for the normal function of cells and the healthy life of human. The dysregulation of calcium was found to be associated with cancer, cardiovascular diseases and various immunological disorders [5 –7]. The cellular calcium is orchestrated with the help of ion channels distributed in the cells. The transient receptor potential (TRP) channels are one of the major proteins which control Ca²⁺ flow inside a cell and are widely distributed in human tissues. In the last two decades TRP channels were explored extensively to understand their role in cancer [1 , 9]. TRP channel proteins belongs to the superfamily of approx. 30 members responsible for the regulation of cation, reported first time in Drosophila melanogaster in 1989 [10, 11]. However, in mammals the TRP channel superfamily is subdivided into six subsections based on sequence homology as- TRPC (Canonical), TRPA (Ankyrin), TRPM (Melastatin), TRPV (Vanilloid), TRPP (Polycystic), and TRPML (Mucolipin). The in-silico analysis revealed that all TRP channels are made of six transmembrane proteins (S1→S6) in which the pore formation occurs between S5 and S6 [12]. Since the discovery of these cation channels the channelopathies (the disease caused due to defects of a channel) have been explored extensively for various diseases including cancer [13, 14]. In this review we are summarizing various TRP channel subfamilies, TRPC and TRPM, for their role in the orchestrating the various hallmarks of cancer.

2 TRP channels and cancer

TRP channels serve as a single integrator by altering membrane potential or intracellular free divalent cations. TRP channels also facilitate the individual cells to feel the changes in a local environment [15]. Carcinogenesis involves the transformation of normal cells to the hyperplastic first, then dysplastic, next neoplastic, and finally transformed into metastatic cells. These transformations are due to mutation in certain key signaling proteins [16]. Out of all channel proteins, TRP proteins have been found to affect a diverse physiological and pathological process [17]. In comparison to normal cells, TRP proteins have amplified or diminished levels of expression in the cancerous cells depending on the cancer stages [16]. The involvement of TRP channels in cancer proliferation, inconsistent differentiation, and reduced apoptosis, hence leading to the rampant cancer growth and invasion of the tumor [17].

2.1 TRPC channel proteins and their role in cancer

Overall, 6 variants of TRPC proteins are reported in humans, divided into two subfamilies based on their functionality and biochemical similarities (TRPC1/TRPC4/TRPC5 and TRPC3/TRPC6/TRPC7). However, in human, TRPC2 is absent and considered a pseudogene. The growing evidences supports that the TRPC channel is engaged in the regulation of most of the cancer hallmarks like proliferation, invasion, migration, apoptosis and survival, presented below in Table 1.

Table 1
Different TRPC channel responsible for the hallmarks of different cancer

Channel Type of cancer Hallmark Outcome Reference

TRPC1 Glioblastoma Migration Activated TRPC1 channels control cell Chemostasis [18]

Breast cancer Proliferation Downregulation of TRPC1 reduced the Ca²⁺ entry & proliferation [19]

Non-small cell lung cancer Proliferation TRPC1 silencing inhibit proliferation &reduce cell growth [20]

Colon cancer Proliferation, migration, survival Upregulation of TRPC1 channel associated with cancer malignancy [8]

TRPC3 Ovarian cancer Proliferation, Tumor formation Downregulation of TRPC3 reduced cell proliferation [21]

Breast cancer (TNBC) Proliferation, Apoptosis resistance Overexpressed TRPC3 regulates Ras GTPase-activating protein 4 through Ca²⁺ directed activation [22]

TRPC4 Medulloblastoma Migration OGR1 enhances expression of TRPC4 leads to migration [23]

TRPC5 Colon cancer Metastasis Overexpression of TRPC5 promote tumor metastasis [24]

TRPC6 Breast cancer Proliferation, migration, invasion Translocation of Orai1 and Orai3 for Ca²⁺ modulation [1]

Esophageal Cancer

Hepatocellular carcinoma Tumor formation, Cell growth TRPC6 inhibition suppressed the tumor formation [25]

Glioblastoma Migration, invasion, Metastasis TRPC6 complex facilitates the effect of TGFβ to promote metastasis [26]

Prostate cancer Cell growth, invasion Proliferation Inhibition of Notch pathway is associated with upregulation of TRPC6 [27]

Proliferation, Cell growth Downregulation of TRPC6 abolished proliferation [28]

Channel	Type of cancer	Hallmark	Outcome	Reference
TRPC1	Glioblastoma	Migration	Activated TRPC1 channels control cell Chemostasis	[18]
	Breast cancer	Proliferation	Downregulation of TRPC1 reduced the Ca²⁺ entry & proliferation	[19]
	Non-small cell lung cancer	Proliferation	TRPC1 silencing inhibit proliferation &reduce cell growth	[20]
	Colon cancer	Proliferation, migration, survival	Upregulation of TRPC1 channel associated with cancer malignancy	[8]
TRPC3	Ovarian cancer	Proliferation, Tumor formation	Downregulation of TRPC3 reduced cell proliferation	[21]
	Breast cancer (TNBC)	Proliferation, Apoptosis resistance	Overexpressed TRPC3 regulates Ras GTPase-activating protein 4 through Ca²⁺ directed activation	[22]
TRPC4	Medulloblastoma	Migration	OGR1 enhances expression of TRPC4 leads to migration	[23]
TRPC5	Colon cancer	Metastasis	Overexpression of TRPC5 promote tumor metastasis	[24]
TRPC6	Breast cancer	Proliferation, migration, invasion	Translocation of Orai1 and Orai3 for Ca²⁺ modulation	[1]
	Esophageal Cancer
	Hepatocellular carcinoma	Tumor formation, Cell growth	TRPC6 inhibition suppressed the tumor formation	[25]
	Glioblastoma	Migration, invasion, Metastasis	TRPC6 complex facilitates the effect of TGFβ to promote metastasis	[26]
	Prostate cancer	Cell growth, invasion Proliferation	Inhibition of Notch pathway is associated with upregulation of TRPC6	[27]
		Proliferation, Cell growth	Downregulation of TRPC6 abolished proliferation	[28]

In a recent study, it was investigated that TRPC1 has an important role in cell migration, glioblastoma cells, in response to platelet-derived growth factor (PDGF) induced chemotaxis [18]. Additionally, the study suggested that the gene silencing by the TRPC1-siRNA has equivalent chemotaxis prohibiting capacity as the SKI-II, a precise blocker of sphingosine kinase (S₁P), has shown in the treated glioblastoma cells [18]. In breast cancer, TRPC1 was found to be associated with the Ca²⁺ entry and the cell proliferation [19]. Interestingly, the study supports that TRPC1 is required for ERK1 and ERK2 phosphorylation which could be connected with breast cancer progression via ERK pathway in association with TRPC1 regulated Ca²⁺ entry as well as calcium-sensing receptor-dependent proliferation breast cancer cells [19]. Calcium entry through TRPC1 plays a decisive role in EGFR activation and further management of its downstream target in non-small cell lung carcinoma (NSCLC) Cell [20]. The TRPC1 silencing induced G_o/G₁ cell cycle arrest, reduces the cell growth and inhibits cell proliferation in the NSCL cells [20]. In another study the upregulation of TRPC1 channel was correlated with malignancy of colon cancer cell. In the study an inhibitor, Difluoromethylornithene (DFMO) which inhibits the TRPC1 channel, was able to decrease the SOCE and overturned the cell proliferation, cell migration as well as apoptotic resistance in the treated colon cancer cells [8]. In a recent study, it was shown that the TRPC3 channel promotes ovarian cancer cell growth [21]. The downregulation of TRPC3 expression led to reduced cell proliferation in the cells. The study was also validated in a xenograft animal model with the aborted TRPC3 expressing cells for the tumor formation [21]. The TRPC3 channel was recently being explored in triple-negative breast cancer (TNBC) cells and the overexpressed protein was targeted by Pqr3 (TRPC3 blocker). Interestingly, the investigators found abrupted proliferation and apoptosis resistance through activation of MAPK pathway which lead to increased cell death and downregulation of RASA4 on membrane [22]. In a recent study, in Medulloblastoma samples it was found that the expression OGR1 (Ovarian cancer G protein coupled receptor 1) encourages the TRPC4 expression which further resulted in the upregulated Ca²⁺- influx and improved cell migration [23]. The evidence supports the role of TRPC4 in cancer hallmarks for invasion and metastasis in pediatric brain tumor [23]. In a study, TRPC5 was found to be overexpressed in colon cancer and the evidence suggested its role in promoting EMT (Epithelial to mesenchymal transition) through HIF-1α-Twist signaling pathway to induce tumor metastasis. The TRPC5 overexpression was found to be associated with overall poorer and metastasis free survival of colon cancer patients [24]. The another member of the TRPC sub-family, TRPC6, was largely explored for channelopathy including cancer cases [1 , 25]. In a study enhanced expression TRPC6 channel was shown in TNBC cells and the knockdown of TRPC6 aborted the invasion, migration and cell proliferation [1]. In addition, the increased expression of TRPC6 channels were observed in oesophageal squamous cell carcinoma (OSCC). The TRPC6 channel obstruction led to inhibition of [Ca²⁺] _i as well as activation of CdC2 kinase in the OSCC cells [25]. The decrease of Ca²⁺ concentration in the cells induced the cycle arrest in G₂ phase and suppressed the cell growth. Interestingly, the TRPC6 channel inhibition suppressed the tumor formation in nude mice [25]. The TRPC6 along with Na⁺/Ca²⁺ exchanger 1 (NCX1) were recently being explored for understanding their role in the regulation of TGFβ expression in hepatocellular carcinoma cells [26]. The investigators found that TGFβ triggers the TRPC6/NCX1 complex formation for the elevated Ca²⁺ concentration in the cytoplasm [26]. In another study TRPC6 was demonstrated for the regulation of glioma cell growth and invasion through the Notch pathway [27]. In a study, the TRPC6 was found to be associated with HGF induced prostate cancer cell proliferation [28].

2.2 TRPM sub-family and their role in cancer

The Transient receptor potential Melastatin (TRPM) is another subfamily of TRP superfamily highly explored for malignancy and physiological processes like night vision, immune responses, heat sensitivity, artery vasoconstriction, taste-sensing mechanism, and insulin excretion, absorption of magnesium, and cold sensation [29]. There are overall eight TRPMs, TRPM 1-8, each dwell 6 transmembrane domain with a pore-forming loop besides N and C-terminal directed toward cytoplasm, which regulates the fluxes of cations. However, the reports are available for TRPM1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM7 and TRPM8 which shows their involvement in the control of cancer-relevant processes such as cell proliferation, migration, invasion, tumor formation, cell growth, and apoptosis in different types of human cancer (given in Table 2). The growing shreds of evidence support that the TRPM proteins possess an oncogenic role which was proven through gene knockdown, knockout, inhibition, or overexpression methodologies in both human cancer cell lines and animal models [29]. Exceptionally, the TRPM1 genes which possess micro-RNA 211 (MiR-211) at its 6th intron position were found to be regulated by MITF, a melanocyte transcription factor [30]. Two independent investigations suggested that both the TRPM1 and the miR-211 expression caused substantial inhibition of growth and reduces invasion in human melanoma [30, 31]. These reports suggested tumor suppressor role of TRPM1 but it should be explored in various other types of cancers. Besides that TRPM2 targeting in oral cancer, prostate cancer, pancreatic cancer and gastric cancer has shown the signs of cure at in vitro levels [32 –34]. The anti-cancer activities of TRPM2 was demonstrated to be associated AKT/PTEN/phosphor-AKT in gastric cancer [34]. Besides, TRPM3 overexpression was reported for enhanced cell growth and regulation of autophagy through increased Ca²⁺-influx followed by activation of AMPK, CAMKK2, and ULK1, and phagophore construction in clear cell renal cell carcinoma [35]. In a recent study the elevated level of TRPM4 protein in prostate cancer was demonstrated to regulate metastasis but not proliferation [36]. Interestingly, TRPM5 expression were corelated with acidic extracellular pH (pH e) induced MMP-9 expression in melanoma cells [37]. The study supports that targeting TRPM5 can reduce the metastasis in some cancer types but not in all. However, TRPM6 was reported for its association with cetuximab induced hypomagnesemia [38]. The largely explored members of TRPM channel sub-family are TRPM7 and TRPM8 for various types of cancers associated channelopathy. Recently, a study demonstrated that hypoxia-induced cell invasion and migration of androgen-independent prostate cancer cells was prohibited by the silencing of TRPM7 gene [39]. The TRP channels are known for the homeostasis of both Ca²⁺ and Mg²⁺ ions [4, 15]. In a study the role of TRPM7 was explored for the regulation of Mg²⁺-dependent pancreatic cancer cell migration upon knockdown [40]. Interestingly, inhibition of cancer invasion and migration upon targeting TRPM7 alone was explored in prostate cancer, pancreatic cancer, breast cancer, renal cancer, glioblastoma, lung cancer and esophageal cancer [39 –45]. The mechanism of the inhibition of migration upon targeting TRPM7 was reported as MAPK pathway in breast cancer and Src and AKT pathway in renal carcinoma [41, 42]. However, the overexpressed TRPM7 in lung cancer was found to be associated with stem cell like behavior (EMT) and the cell migration which was possibly controlled through heat sock protein (Hsp90α) and metalloproteinase-2 (MMP2) signaling pathway [44]. Contradictable results of TRPM7 left us unclear about its procancerous or anti-cancerous properties, as discussed in many studies, but in oesophageal cancer the knockdown of TRPM7 was reported for enhanced proliferation, invasion and migration [45]. The protein was proven to be considered as an independent prognostic marker in human esophageal cancer [45]. Next member of the TRPM sub-family, TRPM8, was extensively investigated in prostate cancer, osteosarcoma, pancreatic cancer, lung cancer, breast cancer, melanoma, oral cancer and esophageal cancer for its pro-cancerous properties as most of the members have shown, except TRPM1 [6 , 46–51]. Reportedly, the protein showed its role in regulation of apoptosis in addition to proliferation and invasion in osteosarcoma and esophageal cancer [47, 52]. Interestingly, in osteosarcoma the knockdown of TRPM8 decreased intracellular calcium followed by suppressed the phosphorylation of p44/p42 and FAK. Furthermore, they concluded that targeting TRPM8 induced apoptosis via the Akt-GSK-3β pathway [47]. Recently, the role of TRPM8 was reported for the immune cell evasion in esophageal cancer [52]. In the study, they co-incubated the T- cells with overexpressed TRPM8 esophageal cells and found that T-cell induced cytotoxicity was reduced. In line with the study, the mechanism reported for the immune evasion in the esophageal cancer was regulated through NFATc-3 (calcineurin-nuclear factor of activated T cells-3) pathway via expression of PD-L1(programmed death ligand 1) [52]. Additionally, when TRPM8 was targeted in lung cancer cells it was reported to control cell adhesion and invasion but proliferation was enhanced in lung cancer cells [49].

Table 2
Different TRPM channel responsible for the hallmarks of different cancer

Channel Type of cancer Hallmark Key Outcome Reference

TRPM1 Melanoma Invasion Upregulation of TRPM1 leads to inhibition of invasion [30]

TRPM2 Prostate cancer Proliferation, Cell growth Downregulation of TRPM2-induced inhibition of proliferation [53]

Pancreatic cancer Proliferation, Invasion, Migration Upregulation of TRPM2 promoted cell proliferation, invasion and migration ability [32]

Gastric cancer Proliferation Downregulation of TRPM2 decreases cell proliferation [34]

Oral cancer Migration Downregulation of TRPM2 inhibits the migration [33]

TRPM3 Renal cell carcinoma Cell growth and autophagy Overexpression of TRPM3 promotes Ca²⁺-influx which leads to activation of AMPK, CAMKK2, and ULK1, and phagophore creation. [35]

TRPM4 Prostate cancer Migration Upregulation of TRPM4 promote cell migration [36]

TRPM5 Melanoma Acidic extracellular(pH_e), Metastasis Targeting TRPM5 reduced pH _e -induced MMP-9 expression [37]

TRPM6 Colon cancer Hypomagnesemia Cetuximab downregulate the Mg²⁺ influx via TRPM6 by inhibiting ERK ½ phosphorylation [38]

TRPM7 Prostate cancer Migration, Invasion downregulation of TRPM7 abolish cell migration, and invasion [39]

Pancreatic cancer Cell migration Downregulation of TRPM7 inhibits intracellular Mg²⁺ fluorescence and cell migration [40]

Breast cancer Migration, invasion TRPM7 regulates migration and invasion [41]

Renal cancer Migration, invasion Silencing TRPM7 reduced migration &invasion [42]

Glioblastoma Cell viability, Proliferation, Invasion, migration, apoptosis Induced apoptosis by silencing TRPM7 activity [43]

Lung cancer Cell viability, Migration, invasion knockdown of TRPM7 suppresses the cell viability, migration and invasion [44]

Esophageal cancer Proliferation, migration, invasion TRPM7 expression was corelated with the survival and act as a prognostic marker [45]

TRPM8 Prostate cancer Proliferation Inhibition of TRPM8 expression and function Reduces proliferation [46]

Osteosarcoma Proliferation, Metastasis, Apoptosis Knockdown of TRPM8 diminishes the cell proliferation & metastasis but then also enhances the apoptosis in cells. [47]

Pancreatic cancer Migration Aberrantly overexpression of TRPM8 channels contributes to the growth and cell invasion [48]

Lung cancer Proliferation, invasion, tumor growth Knockdown of TRPM8 promoted cell proliferation & reduce adhesion and invasion [49]

Breast cancer Proliferation Overexpression of TRPM8 leads proliferation [6]

Melanoma Tumor growth Activation of TRPM8 primes to tumor growth [50]

Oral cancer Migration, invasion Blockage of TRPM8 expression reduces the invasion. [51]

Esophageal cancer Cell viability, proliferation, apoptosis Inhibition of TRPM8 suppressed proliferation and induce apoptosis [52]

Channel	Type of cancer	Hallmark	Key Outcome	Reference
TRPM1	Melanoma	Invasion	Upregulation of TRPM1 leads to inhibition of invasion	[30]
TRPM2	Prostate cancer	Proliferation, Cell growth	Downregulation of TRPM2-induced inhibition of proliferation	[53]
	Pancreatic cancer	Proliferation, Invasion, Migration	Upregulation of TRPM2 promoted cell proliferation, invasion and migration ability	[32]
	Gastric cancer	Proliferation	Downregulation of TRPM2 decreases cell proliferation	[34]
	Oral cancer	Migration	Downregulation of TRPM2 inhibits the migration	[33]
TRPM3	Renal cell carcinoma	Cell growth and autophagy	Overexpression of TRPM3 promotes Ca²⁺-influx which leads to activation of AMPK, CAMKK2, and ULK1, and phagophore creation.	[35]
TRPM4	Prostate cancer	Migration	Upregulation of TRPM4 promote cell migration	[36]
TRPM5	Melanoma	Acidic extracellular(pH_e), Metastasis	Targeting TRPM5 reduced pH _e -induced MMP-9 expression	[37]
TRPM6	Colon cancer	Hypomagnesemia	Cetuximab downregulate the Mg²⁺ influx via TRPM6 by inhibiting ERK ½ phosphorylation	[38]
TRPM7	Prostate cancer	Migration, Invasion	downregulation of TRPM7 abolish cell migration, and invasion	[39]
	Pancreatic cancer	Cell migration	Downregulation of TRPM7 inhibits intracellular Mg²⁺ fluorescence and cell migration	[40]
	Breast cancer	Migration, invasion	TRPM7 regulates migration and invasion	[41]
	Renal cancer	Migration, invasion	Silencing TRPM7 reduced migration &invasion	[42]
	Glioblastoma	Cell viability, Proliferation, Invasion, migration, apoptosis	Induced apoptosis by silencing TRPM7 activity	[43]
	Lung cancer	Cell viability, Migration, invasion	knockdown of TRPM7 suppresses the cell viability, migration and invasion	[44]
	Esophageal cancer	Proliferation, migration, invasion	TRPM7 expression was corelated with the survival and act as a prognostic marker	[45]
TRPM8	Prostate cancer	Proliferation	Inhibition of TRPM8 expression and function Reduces proliferation	[46]
	Osteosarcoma	Proliferation, Metastasis, Apoptosis	Knockdown of TRPM8 diminishes the cell proliferation & metastasis but then also enhances the apoptosis in cells.	[47]
	Pancreatic cancer	Migration	Aberrantly overexpression of TRPM8 channels contributes to the growth and cell invasion	[48]
	Lung cancer	Proliferation, invasion, tumor growth	Knockdown of TRPM8 promoted cell proliferation & reduce adhesion and invasion	[49]
	Breast cancer	Proliferation	Overexpression of TRPM8 leads proliferation	[6]
	Melanoma	Tumor growth	Activation of TRPM8 primes to tumor growth	[50]
	Oral cancer	Migration, invasion	Blockage of TRPM8 expression reduces the invasion.	[51]
	Esophageal cancer	Cell viability, proliferation, apoptosis	Inhibition of TRPM8 suppressed proliferation and induce apoptosis	[52]

3 Conclusions and future direction

Cancer is the second most frightening disease worldwide with approx. 18,078,957 new incidences and 9,555,027 deaths was reported for the year 2018 by the World Health Organization (WHO) as GLOBOCAN 2018 [54]. Cancer is the result of dysregulation of normal cellular function, mainly cell cycle regulation [55]. Recently the concept of ionic balance in association with cellular functions came into picture which has shown the possibility to cause cancer in last two decades. In this review, we explored TRP channels, TRPC and TRPM, for their role in cancer. Decisively, these channels are found to be accountable for various hallmarks of cancer, explored in many cancer types.

3.1 TRPC

Conclusively, TRPC channels are being explored in breast cancer, colon cancer, lung cancer, prostate cancer, ovarian cancer, glioblastoma, liver cancer, oesophageal carcinomas and medulloblastomas. However, TRP channels are known for the regulation of any divalent cations but TRPC1, TRPC4 and TRPC6 were reported for the regulation of intracellular Ca²⁺ influx and SOC. The TRPC1 expression and its oncogenic properties were found to be regulated via ERK pathway for cancer proliferation, metastasis and apoptotic resistance. However, TRPC3 was reported for MAPK pathway as well as downregulated expression of RASA4 on plasma membrane. Interestingly, TRPC4 expression in pediatric brain cancer was found to be associated with OGR1 expression but TRPC5, prognostic marker of poor survival, reported for epithelial to mesenchymal transition through HIF-1a-Twist signaling pathway. The most explored variant of TRPC sub-family is TRPC6, complexed with NCX1 after getting triggered by TGFβ for enhanced Ca²⁺ influx. In addition, TRPC6 was reported for invasion through Notch signaling pathway. Conclusively, TRPC could be an effective target for cancer regulation shown in Fig. 1.

Fig. 1

TRPC channels in cancer: The six TRPC proteins were explored in nine different cancers. In breast cancer, TRPC1, TRPC3 and TRPC6 were explored but except colon cancer and glioblastoma other cancer types were explored for only one type of TRPCs.

3.2 TRPM

In this review we explored the role of TRPM subfamily in melanoma, breast cancer, lung cancer, renal carcinomas, gastric cancer and many others, presented in Fig. 2. Surprisingly we found that the TRPM1 and TRPM7 expression or targeting evidenced their role in tumor suppressive functions in some studies which must be verified in other cancer types. However, TRPM2 was found to be associated with high proliferation, invasion and migration in various cancer types. Interestingly, TRPM2 targeting has given away for the curative signs in prostate cancer, gastric cancer and oral cancer. Unpredictably, among all TRPMs we found very less literatures on TRPM3, TRPM4, TRPM5 and TRPM6 for cancer. The TRPM6 was indirectly associated with cancer treatment side-effect through Mg²⁺-influx dysregulation (hypomagnesemia) due to cetuximab, an EGFR targeting monoclonal antibody, often given in colon cancer treatment. However, TRPM5 have different approach to enhance metastasis i.e., through pH _e . Additionally, we found that the role of the last member, TRPM8, was explored in osteosarcoma, pancreatic cancer, lung cancer, breast cancer, melanoma and few others. In most of the cancer types, TRPM8 targeting were reported for decreased proliferation along with other hallmarks but exceptionally, in lung cancer it was reported for promoting cell proliferation in addition to reduction in cell adhesion and invasion. This report created the controversial role of TRPM8 for proliferation of cancer cells. The role of TRPM8 must be studied in lung cancer for clarification and comparison.

Fig. 2

TRPM channels in cancer: The TRPM channels were explored in prostate cancer, osteosarcoma, gastric cancer, pancreatic cancer and various other types of cancers. Among all, TRPM7 and TRPM8 are the extensively explored members of TRPM subfamily.

Footnotes

Acknowledgments

This work was supported by the Department of Biotechnology, Meerut Institute of Engineering and Technology (MIET), Meerut for individual project.

Conflict of interest

The authors declared no conflict for above discussed topic.

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